The application and validation of biomarkers for lung cancer risk has been a major focus of this laboratory, ultimately impacting upon risk assessment, cancer prevention strategies and understanding of carcinogenic mechanisms. The biomarkers currently under study include genetic polymorphisms for carcinogen activation (CYP2D6, CYP2E1, CYP1A1, and NAT) and detoxification (GSTmu), protooncogenes (L-myc, HRAS-1), and tumor suppressor genes (p53). The formation of human serum antibodies against p53 protein and polycyclic aromatic hydrocarbon-DNA adducts (PAH-DNA adducts) also are being studied, the former representing p53 mutation and the latter representing exposure and determinants of adduct formation. Other biomarkers of interest include urinary mutagenesis and nitrosoacid excretion. This project has determined that the GSTmu null genotype, mechanistically related to decreased detoxification of a number of known and suspected carcinogens, is related to an increase in serum anti-PAH-DNA adducts and PAH-DNA adducts in human lung. It is also related to a decrease in urine mutagenicity. Thus, in two cohorts and for three different biomarkers, a significant cancer risk related to the null GST genotype is suggested. CYP1A1 and CYP2E1 was not related to cancer risk, urinary mutagenesis or nitrosoacid excretion, although CYP2E1 was related to an increase in 7-alkyl-DNA adducts in human lung. Serum anti-p53 antibodies have now been detected in a number of persons with cancer and also is sometimes detectable before clinical evidence of cancer, suggesting that these antibodies might be early tumor markers. Finally, a pilot project for a molecular epidemiology study for lung cancer risk in China has suggested that the risk associated with cooking oils might be related to linolenic acid content, aldehyde emissions or 1,3-butadiene production.